Design of metastatic-derived hybrid lipoosmes for brain drug delivery

The blood-brain barrier (BBB) is a highly selective and dynamic interface separating the central nervous system from the systemic circulation, consisting of tightly interconnected endothelial cells (ECs) that line the capillaries within the brain, along with surrounding cells, such as pericytes and astrocytes. However, its tightly regulated permeability poses a significant challenge for the delivery of therapeutic agents to the brain [1]. Liposomes offer distinct advantages in crossing biological barriers due to their biocompatibility, ability to encapsulate both hydrophilic and hydrophobic drugs, and surface tailoring [2]. Despite these attributes, efficient BBB crossing remains a significant obstacle, requiring innovative functionalization strategies. Brain metastatic cells (BMCs) - such as those derived from melanoma, lung or breast tumors - possess a remarkable ability to traverse the BBB and form secondary tumors in the brain. This behavior is attributed to specific proteins and lipid structures on their cell membranes that interact with BBB ECs to mediate translocation [3]. Inspired by this natural mechanism, membranes derived from BMCs can be used to generate liposomes, leveraging their natural ability to interact with ECs and facilitating BBB penetration [4]. By mimicking their natural strategies for BBB traversal, we aim to develop an efficient drug delivery platform to target brain tumours and overcome the limitations imposed by the BBB. Thus, this study explores the design of metastatic-derived hybrid liposomes (MDHL) obtained from the hybridization of synthetic lipids and plasma membranes fragments from BMCs that can endow the nanoparticles with the unique protein and lipid signatures of these cells. The research demonstrates the stability and functional protein retention of MDHL. A BBB in vitro model confirmed their non-toxic nature and permeability. Nanoparticle Tracking Analysis quantified BBB crossing efficiency, showing promising potential for the application of MDHL as effective drug delivery nanosystems. Future work aims to obtain plasma membrane from different BMCs lines to understand the array of protein and lipid composition for enhanced BBB penetration and drug delivery efficacy.